Process for preparing citrates using organic titanates

ABSTRACT

Citrate esters are formed utilizing organic titanates as a catalyst allowing excess alcohol to be removed. Four citrate esters have been found which provide advantageous plasticizing properties to PVC compositions which include superior toxicity test results and superior soapy water extraction test results. The four citrate esters are: acetyltri-n-hexyl citrate, n-butyryltri-n-hexyl citrate, acetyltri-n-(hexyl/octyl/decyl) citrate, and acetyltri-n-(octyl/decyl) citrate. Articles formed from the PVC plasticized mixtures are extremely useful in the medical or health care field as they demonstrate a low order of toxicity.

This is a continuation of application Ser. No. 866,463 filed May 22,1986, now U.S. Pat. No. 4,710,532, which was a continuation of pendingpatent application Ser. No. 711,284 filed March 13, 1985, now abandoned,which was a continuation-in-part of application Ser. No. 619,583 filedJune 11, 1984, also now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

Citrate esters are useful as plasticizers for polyvinyl chloride (PVC)resins as certain of these esters provide a low order of toxicity whencompared to phthalate esters which have been conventionally used. Otheradvantages have been noted using certain citrate esters as plasticizersin PVC compositions and articles, including improved resistance to soapywater extraction and low temperature and transport properties.

Medical articles formed from PVC compositions utilizing certain citrateesters as plasticizers provide an improved environment for whole bloodand blood platelets compared to PVC formulations utilizing conventionalplasticizers. Such medical articles may consist of:

1. bags for the storage of whole blood, packed red cells, platelets andplasma;

2. intravenous tubing for the transportation of blood, blood productsand crystalloid intravenous fluids;

3. indwelling intravenous and intra-arterial catheters; and

4. tubing-flexible having contact with whole blood as used in:

(a) renal dialysis devices;

(b) corpuscular oxygenators as used in open heart surgery;

(c) membrane oxygenators for pulmonary failures;

(d) phagocytosis for the collection of platelets and leucocytes fortransfusions; and

(e) intensive plasma exchange devices.

The preparation of the citrate esters has been found to be significantlyenhanced by the utilization of certain organic titanate catalysts whichallow the excess alcohol to be removed after the esterification step.

2. Description Of The Prior Art And Objectives Of The Invention

Citrate esters commercially produced using citric acid have long beenavailable and have been used as plasticizers for PVC resins. However,the performance of articles produced from the PVC resin compositionswhether utilizing citrate esters known to date or conventional phthalateplasticizers have had many inherent disadvantages. For example,medical-grade PVC compositions are used to form blood bags, tubing and avariety of health-related articles and in recent years toxicity has beena major concern for manufacturers of such articles. Recent reports haveidentified di-2-ethylhexyl phthalate (DEHP) or (DOP) anddi-2-ethyl-hexyl adipate (DEHA) as hepatocarcinogens in rodents.

In vitro studies have demonstrated significant growth inhibition ofhuman diploid fibroblasts at DEHP concentrations that are found in wholeblood stored for 21 days and platelets stored for 24 hours inconventional blood bags. Transfusion studies in monkeys revealedphysiological and histological liver abnormalties for up to 26 monthsafter the cessation of transfusions. Patients undergoing kidney dialysisreceived an amount of DEHP approximately 10 to 20 times that whichproduced liver damage in the monkeys. DEHP has also been demonstrated tobe a peroxisome proliferator and probably a hepatic carcinogen inanimals. These results were largely supported by the standard NationalCenter Institute National Toxicology Bioassay Program Study in rats andmice.

Industry's attempt at developing alternative PVC plasticizers have beenmet with limited success. Two of the polymers utilized in a recentcomparative study, PVC-TOTM and polyolefin are presently approved forthe storage of blood platelets for up to seven days. This is based onboth in vivo survival and function studies and their improved gaspermeability as compared to PVC-DEHP. The above formulations (PVC-DEHPand polyolefins) and all others attempted to date have not provensuitable for red cell survival studies. The formulations mentioned alsoshow an increase in osmotic fragility of red cells, elevated plasmahemoglobin levels, and red cell potassium levels. This would implicatered cell membrane lesions.

While certain of the phthalates have excellent plasticizing qualities,their suspected carcinogenic nature renders them doubtful candidates forfuture medical-grade uses. As an alternative, known citric acid esterssuch as acetyltri-n-butyl and tri-n-butyl citrate were tried as PVCplasticizers in medical-grade applications but it was determined thatthese compounds were not entirely satisfactory due to their high soapywater extraction percentages and would therefore not be useful in manymedical area applications. Also, it has been found that new productiontechniques had to be devised for the newer citric acid esters which weredetermined to have suitable toxicity and physical characteristics whenused as PVC plasticizers.

It is therefore an objective of the present invention to provide PVCplasticizers which provide superior toxicity test results in biologicalstudies.

It is also an objective of the present invention to provide plasticizersfor PVC compositions which can be processed without difficulty usingconventional extrusion, calendering, or plastisol techniques.

It is yet another objective of the present invention to provide newcitric acid esters namely: acetyltri-n-hexyl citrate,n-butyryltri-n-hexyl citrate, acetyltri-n-(hexyl/octyl/decyl) citrate,and acetyltri-n-(octyl/decyl) citrate which can be used as plasticizershaving desirable physical characteristics when imparted into PVCcompositions.

It is still another objective of the present invention to provide PVCcompositions and formed articles therefrom having superior results intoxicology studies concerning dermal toxicity, oral toxicity and geneticassays.

Another objective of the invention is to provide a medical article andprocess for making the same such as a blood bag which will provide animproved environment for containing whole blood or blood platelets.

It is also an objective of the present invention to provide a newprocess for the manufacture of the four new citric acid esters utilizingorganic titanates to provide economical and efficient productionmethods.

Others objectives and advantages of the present invention will bedemonstrated to those skilled in the art as set forth in detail below.

SUMMARY OF THE INVENTION

Citrate esters of the formula: ##STR1## where R₁, R₂, and R₃ ═CH₃ to C₁₈H₃₇

R₄ ═CH₃ to C₇ H₁₅

and more specifically acetyltri-n-hexyl citrate, n-butyryltri-n-hexylcitrate, acetyltri-n-(hexyl/octyl/decyl) citrate, andacetyltri-n-(octyl/decyl) citrate are produced utilizing an organictitanate catalyst and such esters have been found useful asmedical-grade plasticizers in PVC compositions. The plasticizers have alow order of toxicity and inpart to PVC the proper balance of physicalproperties needed in health care and medical-grade uses. The productionsteps for the citric acid esters include esterification, removal of anyexcess alcohol and thereafter, alkoxylation. Conventional neutralizationand finishing steps are then carried out. The alkoxylation step iscarried out at a temperature less than approximately 110° C.

A PVC resin can be combined with one of the above-mentioned citric acidesters, along with suitable stabilizers and lubricants, to form aplasticized PVC which can be extruded, calendered or otherwise processedinto suitable articles of manufacture including blood bags, tubing andother products. Articles so made have a low order of toxicity andprovide superior extraction properties, particularly in soapy waterextraction tests. The soapy water extraction test is a standard test,the results of which closely resemble the results obtained with bodyfluids such as human blood.

Medical articles formed from PVC compositions employ the above mentionedcitrate acid esters demonstrate improved stability characteristics whenused for storing whole blood or blood platelets.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 demonstrates a typical blood bag formed with a citrateplasticizer of the present invention; and

FIG. 2 shows an end view of the blood bag of FIG. 1.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The four preferred forms of the citrate esters are as follows: ##STR2##

The preferred method of manufacture of the above-identified citrateesters comprises esterification of the proper alcohol (such as n-hexylalcohol for acetyltri-n-hexyl citrate) with citric acid in the presenceof the organic titanate, tetra-n-butyl titanate, removal of any excessn-hexyl alcohol, and then acetylation of the esters produced with aceticanhydride. The acetylation takes place at a temperature of belowapproximately 110° C. Tetra-n-buytyl titanate is preferred since theester interchange which takes place between the titanate alkyl groupsand citrate alkyl groups does not result in the introduction of alkylgroups not normally present in the citrate esters.

The preferred PVC composition comprises blending and milling a mediummolecular weight PVC resin with one of the above citrate esters on a twoto one ratio, resin to plasticizer, along with stabilizers, lubricantsand extenders as required. Articles manufactured from the preferred PVCcompositions include blood bags, tubing and other articles for themedical and health care fields.

A medical article such as a blood bag may be made from medical gradecomponents to form a PVC composition having a PVC resin and citrateplasticizer with other ingredients as follows:

    ______________________________________                                                            Parts By Weight                                           ______________________________________                                        (a)   PVC resin having an inherent                                                                      100                                                       viscosity of .97 -(b)                                                                             n-butyryltri-n-hexyl citrate 50                     (c)   epoxidized soybean oil                                                                            10                                                  (d)   stabilizer Ca/Zn    1                                                   (e)   lubricant (stearic acid)                                                                          .1                                                  ______________________________________                                    

The components are blended by conventional methods and fused. Thecomponents are mixed and fused at temperature in the range of 310°-360°F. by conventional means such as by use of a blender, followed bypelletizing from an extruder. The pellets are then re-fused and mixed inan extruder and film, molded articles, etc. are produced from the secondextrusion.

Film stock can then be cut and sealed together to form bags for thestorage of whole blood, packed red cells, platelets, plasma andintravenous solutions. Such a blood bag generally consists of atransparent pouch having one or more openings for filling, emptying orfor tube insertion.

DETAILED DESCRIPTION OF THE INVENTION

Certain citrate esters, namely acetyltri-n-hexyl citrate,n-butyryltri-n-hexyl citrate, acetyltri-n-(hexyl/octyl/decyl) citrateand acetyltri-n-(octyl/decyl) citrate have been found to be particularlyuseful in medical applications when compounded with PVC resins throughconventional plastisol, calendering or extrusion techniques. Suchplasticized PVC exhibits good clarity, good low temperature properties,low volatility and low extractability into various media. Also, a loworder of acute toxicity has been shown and complete compatibility withmedium molecular weight PVC resins make the four named esters unique andvaluable. Studies have shown that the four citrate esters are not toxicsubstances, primary skin irritants or ocular irritants to unrinsed eyesand oral administration has produced no signs of systemic toxicity andhas shown no mortality in fasted mice or rats. Genetic toxicology assaysfor detecting mutagenic activity at the gene or chromosomal level haveshown that these esters do not induce gene mutation in either microbialcells or in mammalian cells in vitro or chromosomal mutation in vivo orin vitro. Studies have also shown that under in vivo conditions, thesecitrate esters hydrolyze rapidly and completely in concentrations atexpected realistic levels of human exposure.

Preparation of the citrate esters are as follows:

EXAMPLE 1 Preparation of acetyltri-n-hexyl citrate

330 lbs. of n-hexyl alcohol, 180 lbs. of citric acid and 1.54 lbs. oftetra-n-butyl titanate and 15 gallons of heptane are charged to a vesselequipped with agitator, thermometer, vapor column, condenser and adecanter set to allow removal of water formed during the reaction whilerefluxing heptane. The esterification is effected at 140° C. Duringesterification water is periodically removed from the decanter in orderto maintain proper temperature and reaction rates. The esterification iscontinued until the esterification mixture tests 0.5% maximum aciditycalculated as citric acid. Next, the vessel is cooled to 120° C. and anywater is removed from the separator and any heptane therein is alsoremoved for future use. The reflux line of the vessel is closed andpressure on the system is reduced slowly. The kettle is heated again to140° C. and steam is introduced to help remove any residual alcohol.This vacuum steam stripping is continued until alcohol cannot bedetected by conventional laboratory tests. When no more alcohol can befound, the steam is discontinued and the temperature is reduced to 100°C. and the vacuum is broken with nitrogen gas.

Next, 0.4 lb. concentrated sulfuric acid (H₂ SO₄) is charged into thevessel after which it is sealed and approximately 107 lbs. of aceticanhydride (in a determined molar amount) are added at a slow rate sothat the temperature does not exceed 110° C. When all the anhydride hasbeen added, agitation of the mix continues for approximately one houruntil the acetylation reaction has been completed.

Next, a full vacuum is put on the system and enough heat is added fordistillation to proceed at a suitable rate. This step continues untilacetic acid is shown to be 5% or less by conventional lab testswhereupon the mixture is cooled to 75° C. for neutralization.

The remaining steps of neutralization, bleaching, washing, etc. arecarried out as in conventional esterification processes.

EXAMPLE 2 Preparation of n-butyryltri-n-hexyl citrate

The vessel used in example 1 is again charged with 330 lbs. of n-hexylalcohol, 180 lbs. of citric acid and 1.54 lbs. of tetra-n-butyltitanate. Esterification is carried out as in example 1 as is theheptane-alcohol strip. Butyrylization is thereafter done with theaddition of 0.4 lbs. of concentrated sulfuric acid and 166 lbs. ofn-butyryic anhydride as shown above in the acetylation process. Thebutyric acid may be removed as shown above or by neutralization.

Examples 1 and 2 produce esters with the following characteristics:

    ______________________________________                                                     Acetyltri-n-hexyl                                                                           n-Butyryltri-n-hexyl                               Property     Citrate       Citrate                                            ______________________________________                                        ANALYTICAL DATA                                                               Purity wt %  99            99                                                 Color APHA   50 max.       50 max.                                            Neut. No. mg KOH/g                                                                         0.2 max.      0.2 max.                                           Moisture K.F.                                                                              0.25 max.     0.25 max.                                          S.G. @ 25/25° C.                                                                    1.0045-1.0055 0.991-0.995                                        R.I. @ 25/25° C.                                                                    1.445-1.447   1.444-1.448                                        Viscosity @ 25° C. cps                                                              25-35         25-35                                              Odor @ 25° C.                                                                       Little or none                                                                              Little or none                                     ______________________________________                                        Heat Stability                                                                (2 Hrs. @ 150° C.)                                                     Color APHA   50-60         50-60                                              Neut. No. mg KOH/g                                                                         0.2 max.      0.2 max.                                           Odor @ 25° C.                                                                       Mild          Mild                                               ______________________________________                                    

In conventional esterification processes, alcohol stripping can be donewhen acid catalysts such as sulfuric acid, methanesulfonic acid orp-toluenesulfonic acid are used without harmful consequences. However,in the production of the citrate esters of the present invention it hasbeen found that alcohol stripping cannot be done when these acidcatalysts are used due to aconitate formation, poor color, yield andother purity problems. The process of the present invention offers adistinct advantage over the conventional process.

Also, other organic titanate catalysts can be used to produce the four(4) esters of this invention such as tetrakis-2-ethylhexyl titanatealthough superior results have been demonstrated using tetra-n-butyltitanate.

    ______________________________________                                        PREPARATION AND TESTING OF PVC COMPOSITIONS                                                           PARTS BY                                              FORMULATION             WEIGHT                                                ______________________________________                                        Resin (Medium Molecular Weight PVC)                                                                   100                                                   Plasticizer             50                                                    Stabilizer (Calcium/Zinc)                                                                             2.5                                                   Lubricant (stearic acid)                                                                              0.25                                                  ______________________________________                                    

The above formulation was blended and milled for 5-10 minutes at 325° to340° F. The milled stock was pressed (3 min. at 340°-360° F. and 32,000psi) to 40- and 70-mil sheets, and aged for 48 hours at room temperaturefor evaluation. All tests were made with samples cut from 70-mil pressedstock except for extraction tests which were obtained on 40-mil samples.The performance data was obtained by accepted ASTM methods withmodifications as detailed below

    ______________________________________                                        Tensile Strength                                                                              Determined with Instron TT, 1100                              Ultimate Elongation                                                                           series (2 in./min.) using a                                   Modulus (100% elongation)                                                                     dumbbell-shaped specimen. Test                                (ASTM D638)     carried out at 70° ± 5° F.                   Hardness        Determined with Shore                                         (ASTM D676)     Durometer A (10 sec.) at                                                      75° ± 5° F.                                  Torsional Flex (T.sub.4 and T.sub.f)                                                          Determined with Torsion Flex                                  (ASTM D1043)    Tester of Clash and Berg design.                                              T.sub.4 is the temperature at which                                           the Modulus of Rigidity is 10,000                                             psi; T.sub.f is the temperature at                                            which the Modulus of Rigidity is                                              100,000 psi.                                                  Brittle Point   Determined by impact method using                             (ASTM D746)     Scott Tester, Model E.                                        Volatile Loss (A/C)                                                                           Determined on specimens 2 inches in                           (ASTM D1203)    diameter heated in activated carbon                                           at 70° C. for 24 hours. Results                                        are expressed as percent of                                                   plasticizer lost.                                             Water extraction (Tap)                                                                        Determined on specimens 2 inches                              Soapy Water Extraction                                                                        in diameter suspended in                                      (1% Ivory Flakes)                                                                             appropriate liquid at 60° C. for                       Oil Extraction  24 hours. Results are expressed as                            (ASTM NO. 3)    percent of plasticizer lost.                                  Migration Loss (silica)                                                                       Determined on specimens 2 inches                                              in diameter heated in silica                                                  (100 mesh), at 70° C. for 24 hours.                                    Results are expressed as percent of                                           plasticizer lost.                                             Volatile Loss (air)                                                                           Determined by Oven Method                                                     (24 hr. at 100° C.) on specimens                                       2 inches in diameter. Results are                                             expressed as percent of plasticizer                                           lost.                                                         ______________________________________                                    

                                      TABLE A                                     __________________________________________________________________________    (PLASTICIZER PERFORMANCE DATA)                                                PLASTICIZER     DEHP                                                                              DEHA                                                                              #1  #2  #3  #4  #5                                    __________________________________________________________________________    HARDNESS                                                                      Durometer A, 10 Sec.                                                                          79  78  78  81  81  87  87                                    TENSILE, psi    2748                                                                              1797                                                                              2862                                                                              2978                                                                              2924                                                                              2743                                                                              2789                                  ULTIMATE                                                                      ELONGATION, %   395 414 400 390 427 364 374                                   100% MODULUS, psi                                                                             1368                                                                              1092                                                                              1348                                                                              1574                                                                              1362                                                                              1656                                                                              1704                                  T.sub.4 (10,000 psi),                                                         °C.      -8.4                                                                              -30.8                                                                             -7.6                                                                              -9.1                                                                              -11.9                                                                             -6.9                                                                              -4.0                                  T.sub.f (100,000 psi),                                                        °C.      -38.8                                                                             -66.5                                                                             -35.6                                                                             -41.6                                                                             -48.7                                                                             -53.1                                                                             -59.7                                 BRITTLE POINT, °C.                                                                     -24.5                                                                             -56.5                                                                             -18.5                                                                             -26.0                                                                             -33.5                                                                             -36.8                                                                             -37.8                                 VOLATILE LOSS, (air), %                                                                       4.8 7.1 12.1                                                                              2.6 1.7 .3  .1                                    VOLATILE LOSS, (A/C), %                                                                       3.4 7.6 7.0 1.7 1.4 2.8 4.5                                   WATER EXTRACTION, %                                                                           .7  1.5 1.2 1.9 1.7 1.5 3.3                                   SOAPY WATER                                                                   EXTRACTION, %   2.7 11.0                                                                              9.5 5.4 2.2 3.4 2.4                                   OIL EXTRACTION, %                                                                             11.4                                                                              34.7                                                                              10.9                                                                              13.8                                                                              15.7                                                                              15.2                                                                              19.3                                  SILICA GEL MIGRATION, %                                                                       12.2                                                                              23.0                                                                              17.0                                                                              4.4 3.6 4.8 7.4                                   __________________________________________________________________________     #1  acetyltrin-butyl citrate                                                  #2  acetyltrin-hexyl citrate                                                  #3  nbutyryltri-n-hexyl citrate                                               #4  acetyltrin-(hexyl/octyl/decyl) citrate                                    #5  acetyltrin-(octyl/decyl) citrate                                     

The plasticizer performance data in Table B demonstrates the results oftests with citric esters/expoxidized soybean oil (ESO) blends. ESO iscommonly used in conjunction with DEHP at levels in the range of 1-5%based on DEHP as an aid in stabilization. The ratio of 2.5/97.5ESO/citrate was used as a base point in the studies. Test results onthis combination are shown in column 1. A significant improvement inproperties, particularly soapy water extraction is noted.

                                      TABLE B                                     __________________________________________________________________________    (PLASTICIZER PERFORMANCE DATA)                                                PLASTICIZER     2.5                                                                             ESO                                                                              20                                                                              ESO                                                                              40 ESO                                                                             40                                                                              ESO                                                                              40                                                                              ESO                                     PERCENTAGES:   97.5                                                                             #2 80                                                                              #2 60 #2                                                                              60                                                                              #3 60                                                                              #5                                      __________________________________________________________________________    HARDNESS,                                                                     Durometer A, 10 Sec.                                                                          81   80   80   81   85                                        TENSILE, psi    2907 3010 3079 3165 3097                                      ULTIMATE                                                                      ELONGATION, %   422  424  420  428  395                                       100% MODULUS, psi                                                                             1415 1429 1491 1514 1779                                      T.sub.4 (10,000 psi)                                                          °C.      -9.5 -7.8 -7.7 -8.2 -5.4                                      T.sub.4 (100,000 psi)                                                         ° C.     -41.8                                                                              -41.3                                                                              -39.3                                                                              -41.8                                                                              -50.3                                     BRITTLE POINT, °C.                                                                     -26.5                                                                              -25.5                                                                              -20.5                                                                              -24.5                                                                              -26.5                                     VOLATILE LOSS, (Air), %                                                                       2.4  2.1  1.5  .8   .5                                        VOLATILE LOSS, (A/C), %                                                                       1.3  1.6  1.4  .9   1.1                                       WATER EXTRACTION, %                                                                           1.3  .9   .6   .8   1.0                                       SOAPY WATER                                                                   EXTRACTION, %   2.9  2.9  6.4  4.8  3.8                                       OIL EXTRACTION, %                                                                             13.0 11.6 10.1 10.0 12.9                                      SILICA GEL MIGRATION, %                                                                       5.7  5.3  4.7  4.0  2.5                                       __________________________________________________________________________     ESO  Ester/epoxidized Soybean Oil                                             #2  acetyltrin-hexyl citrate                                                  #3  nbutyryltri-n-hexyl citrate                                               #5  acetyltrin-(octyl/decyl) citrate                                     

Since ESO is less expensive than citrates, a reduction in plasticizercost results if ESO can be substituted for part of the citrates. Resultsof tests with higher ESO/citrate ratios as shown in columns 2-5 of TableB and a significant improvements in properties up to and perhaps beyondthe ratio of 20/80 ESO/citrate ratio as shown.

In vitro evaluation of whole blood and platelets has been undertaken inblood bags prepared with PVC compositions plasticized withdi-2-ethylhexyl phthalate (DEPH), or tri-2-ethylhexyl trimellitate(TOTM) and compared to bags utilizing the citrate esters of thisinvention. The results demonstrate in Table C the improvement in wholeblood and platelet characteristics when stored in the PVC blood bagsformed with the improved citrate esters. In these studies the decreasedamounts of glucose demonstrate the increased consumption by the livingblood cells as shown below:

                                      TABLE C                                     __________________________________________________________________________    Glucose mg/dl                                                                             Days Stored                                                       Plasticizer                                                                           Sample                                                                            0  7     22    29    36                                           __________________________________________________________________________    DEHP    1   625                                                                              544   277   260   211                                          DEHP    2   625                                                                              552   285   249   215                                          DEPH    3   625                                                                              552   285   256   221                                          Mean ± SEM                                                                             625                                                                              549 ± 2.5                                                                        282 ± 2.9                                                                        254 ± 3.3                                                                        215 ± 3.1                                 TOTM    1   625                                                                              559   277   237   191                                          TOTM    2   625                                                                              559   267   232   189                                          TOTM    3   625                                                                              548   270   234   191                                          Mean ± SEM                                                                             625                                                                              555 ± 3.8                                                                        271 ± 2.9                                                                        234 ± 1.4                                                                        190 ± 0.4                                 *Citrate Ester                                                                        1   625                                                                              548   262   220   167                                          *Citrate Ester                                                                        2   625                                                                              534   257   217   174                                          *Citrate Ester                                                                        3   625                                                                              559   260   222   174                                          Mean ± SEM                                                                             625                                                                              547 ± 7.3                                                                        260 ± 1.4                                                                        220 ± 1.4                                                                        172 ± 2.1                                 __________________________________________________________________________     *n-butyryltri-n-hexyl citrate                                            

As shown in Table D below there was a 47% decrease in platelet count ina PVC bag utilizing a polyolefin polymer, a 38% decrease in a PVC bagplasticized with TOTM and only a 25% decrease in a PVC bag plasticizedwith the new citrate esters following 7 days of storage.

                  TABLE D                                                         ______________________________________                                        PLATELET COUNT (× 10.sup.9 /ml)                                         Blood Bag       Days Stored                                                   Polymer         0       1       5      7                                      ______________________________________                                        POLYOLEFIN  1       1.41    1.33  0.78   0.76                                             2       1.41    1.30  0.81   0.78                                 PVC-TOTM    1       1.41    1.34  1.04   0.87                                             2       1.41    1.33  0.90   0.89                                 PVC-n-butyryltri-                                                                         1       1.41    1.34  1.27   1.13                                 n-hexyl citrate                                                                           2       1.41    1.38  1.34   0.97                                 ______________________________________                                    

These test results show a greater platelet survival in the PVCcompositions plasticized with the new citrate esters than with thepolyolefin or PVC-TOTM compositions.

PVC compositions suitable for extruding tubing, calendering into sheetsor film for formation of blood bags and for other medical articlesincludes a plasticizer of the general formula: ##STR3## where R₁, R₂ andR₃ ═CH₃ to C₁₈ H₃₇

R₄ ═CH₃ to C₇ H₁₅

which is blended into a PVC composition having medical grade or FDAapproved components including a medium molecular weight PVC resin asdetermined by viscosity, with an inherent viscosity range of the PVCresin approximately 0.90 to 1.20; a calcium/zinc stearate stabilizersold under a number of trademarks and a lubricant such as stearic acid.Additionally, the medical article can be formed from a PVC compositionin which an epoxidized soybean oil can be added in the range of 0 to 30parts by weight. A starting formulation may contain:

    ______________________________________                                        Components         Parts By Weight                                            ______________________________________                                        (a)    PVC resin (0.90 to 1.20                                                                       100                                                           inherent viscosity)                                                    (b)    Citrate ester   40 to 70                                               (c)    Epoxidized soybean oil                                                                         0 to 30                                               (d)    Stabilizer       .5 to 5.0                                             (e)    Lubricant       .050 to 0.5                                            ______________________________________                                    

A typical blood bag 10 containing platelets 15 with tubing 11 formedwith citrate plasticizer of the invention is shown in FIGS. 1 and 2.Spouts 12 and 13 may be used for filling or emptying bag 10 and spout 13is shown with tubing 11 inserted therein. Bag 10 is formed from a PVCcomposition of the invention by heat sealing panels cut from PVC sheetsof suitable thickness as conventionally produced in the table. Tubing 11is made from a PVC composition utilizing a citrate ester of theinvention and may be extruded or otherwise shaped to the desiredthickness, diameter and length.

Various other PVC compositions can be formulated and the examples andillustrations shown herein are for illustrative purposes and are notintended to limit the scope of the invention.

I claim:
 1. A method of producing acetyltri-n-hexyl citrate comprisingthe steps of: heating n-hexyl alcohol and citric acid in the presence ofan organic titanate at a temperature of approximately 140° C. to effectesterification, removing the excess n-hexyl alcohol and acetylating theester by adding acetic anhydride and sulfuric acid while maintaining thetemperature below approximately 110° C. until the acetylation reactionis complete.
 2. The method of claim 1 wherein said organic titanate istetra-n-butyl titanate.
 3. The method of claim 1 wherein removing theexcess alcohol consists of removing the alcohol by steam stripping.
 4. Amethod of producing n-butyryltri-n-hexyl citrate comprising the stepsof: heating n-hexyl alcohol and citric acid in the presence of anorganic titanate at a temperature of approximately 140° C. to effectesterification, removing the excess n-hexyl alcohol and butyrylating theester by adding n-butyryic anhydride and sulfuric acid while maintainingthe temperature below approximately 110° C. until the butyrylizationreaction is complete.
 5. The method of claim 4 wherein said organictitanate is tetra-n-butyl titanate.
 6. The method of claim 4 whereinremoving the excess alcohol consists of removing the alcohol by steamstripping.